This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alpha-1-antitrypsin-AAT deficiency is a hereditary disorder that affects approximately 100,000 individuals in the U.S. and 1-3% of individuals with COPD. AAT deficiency can lead to early emphysema and liver disease. The most common genetic cause of AAT deficiency is the abnormal allele PiZ, Glu324Lys. This Z mutation leads to AAT protein misfolding and polymerization. For years the cause of emphysema was assumed to be due only to the lack of AAT leading to proteolytic destruction of the lung parenchyma. However, preliminary data from our laboratory suggests macrophages with the allele are dysfunctional and may contribute to the development of lung damage. We hypothesize that misfolded intracellular Z AAT lowers the threshold for initiation of inflammation and impairs the ability of macrophages to resolve inflammation. We will evaluate this hypothesis by collecting peripheral blood monocytes, pulmonary function tests, and C-reactive protein levels from normal individuals-PIMM as well as individuals with mutant alleles for AAT, PIMZ, PISZ, and PIZZ. Using monocyte-derived macrophages, we will perform several experiments evaluating macrophage function and response to inflammatory stimuli from AAT deficient individuals compared to non-deficient controls. We will also study various stages of monocyte maturation to macrophages in order to better understand the monocyte-macrophage maturation process and its implication to this model of research.